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Abstract

The Ca2+-independent transient outward potassium current (Ito) contributes to the early phase of action potential repolarization in many species, but the functional contribution of the current to repolarization in human ventricular myocytes is poorly understood. We performed voltage-clamp experiments to detail the time- and voltage dependent properties of Ito in epicardial (n = 92), endocardial (n = 60) and sub-endocardial (n = 61) myocytes isolated from non-failing human left ventricles (n = 55), and used these results to construct an Ito model for use in dynamic clamp experiments to assess directly the contribution of Ito to action potential (AP) repolarization. Initial current clamp recordings reveal that epicardial (n = 34) and endocardial (n = 33) cells display a “notch,” separating the peak of the AP from the plateau, whereas the notch is not evident in APs recorded from sub-endocardial (n = 19) myocytes. In dynamic clamp recordings from epicardial and endocardial myocytes, addition or subtraction of the modeled Ito robustly hyperpolarized or depolarized, respectively, the notch potential; Ito subtraction also affected the plateau potential. In subendocardial myocytes, addition of Ito hyperpolarized the notch potential, with a more robust effect on the plateau than that seen in epicardial and endocardial APs. Gain-of-function mutations which increase Ito density and slow Ito inactivation have been associated with Brugada syndrome. Additional dynamic clamp experiments revealed that adding a modeled Ito with slower inactivation results in collapse of the AP during the early repolarization phase, an effect that would contribute to increased arrhythmia susceptibility, as seen in Brugada syndrome. Additional AP clamp experiments were completed to assess the contribution of Ito to the regulation of ventricular Ca2+ currents (ICa). Control AP waveforms and AP waveforms in which the notch potential was augmented or attenuated were used as command potentials. These experiments revealed that the notch dramatically impacts ICa, and that ICa amplitudes are decreased markedly when the notch is attenuated.